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Originally published as Genetics Published Articles Ahead of Print on February 1, 2008.

Genetics, Vol. 178, 711-723, February 2008, Copyright © 2008
doi:10.1534/genetics.107.081331

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Functional Interactions Between Sae2 and the Mre11 Complex

Hee-Sook Kim*, Sangeetha Vijayakumar*, Mike Reger{dagger}, Jacob C. Harrison{ddagger}, James E. Haber{ddagger}, Clifford Weil{dagger} and John H. J. Petrini*,§,1

* Laboratory of Chromosome Biology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, {ddagger} Rosenstiel Center and Department of Biology, Brandeis University, Waltham, Massachusetts 02454, {dagger} Department of Agronomy, Whistler Center for Carbohydrate Research, Purdue University, West Lafayette, Indiana 47907 and § Weill Medical College, Cornell University Graduate School of Medical Sciences, New York, New York 10021

1 Corresponding author: Laboratory of Chromosome Biology, MSKCC, 1275 York Ave., RRL 901C, New York, NY 10021.
E-mail: petrinij{at}mskcc.org

The Mre11 complex functions in double-strand break (DSB) repair, meiotic recombination, and DNA damage checkpoint pathways. Sae2 deficiency has opposing effects on the Mre11 complex. On one hand, it appears to impair Mre11 nuclease function in DNA repair and meiotic DSB processing, and on the other, Sae2 deficiency activates Mre11-complex-dependent DNA-damage-signaling via the Tel1–Mre11 complex (TM) pathway. We demonstrate that SAE2 overexpression blocks the TM pathway, suggesting that Sae2 antagonizes Mre11-complex checkpoint functions. To understand how Sae2 regulates the Mre11 complex, we screened for sae2 alleles that behaved as the null with respect to Mre11-complex checkpoint functions, but left nuclease function intact. Phenotypic characterization of these sae2 alleles suggests that Sae2 functions as a multimer and influences the substrate specificity of the Mre11 nuclease. We show that Sae2 oligomerizes independently of DNA damage and that oligomerization is required for its regulatory influence on the Mre11 nuclease and checkpoint functions.






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